Development of PAR2 Pepducins as a Novel NASH Treatment

Non alcoholic steatohepatitisNASHis characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosiscirrhosis and high mortality ratesNASH is frequently associated with other common metabolic abnormalitiessuch as insulin resistance and visceral obesityLiver transplantation is currently the only effective therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments to dateProtease activated receptorPARis a signaling receptor that is highly abundant in liver stellate cellshepatocytes and inflammatory cells which controls fibroticinflammatory and metabolic processes that lead towards severe NASH and liver cirrhosisThe cell penetratinglipidated PARinhibitor OAiwas developed using our proprietary PepducinTM technologyPepducinTM technology offers a unique opportunity to target the intracellular surface of recalcitrant G protein coupled receptorsGPCRssuch as PARwith exquisite specificitypotency and long half liveswith prolonged drug exposure to the target tissuenamely liverOAi is an advanced anti fibrotic antiinflammatory drug candidate that blocks PARsignaling in hepatic stellateinflammatory cells and hepatocytesIn the pastyearswith Fast Track support from the NIDDKOasis Pharmaceuticals successfully formulated and produced cGMP OAi atpurity and high stabilityIn in vivo efficacy studiesOAi significantly reduced fatty liver steatosis lobular inflammation ballooning injuryNAS scoreand ALT levels byand gave complete suppression of AST in mouse models of diet induced NASH to the same level of protection afforded by PARdeficiencyOAi afforded highly significant suppression of weight gainliver weightTGssteatosis and development of liver tumor foci in amonth DEN NASH model in mice fed a HFDDelayed OAi treatment gave a significantsuppression of severe liver fibrosis induced byweeks of CClexposureInday repeat dose safety toxicology studiesOAi was safe and tolerated in dogs and in rat GLP studies with no evidence of liverheartkidneylungbone marrowor other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic doseThe translational studies in this Phaseb application provide a rapid clinical validation and accelerate the commercialization of OAi for the treatment of NASH patients in collaboration with Duke Medical Center and Tufts Medical CenterAimwill complete the IND Data Package for OAi in yearof funding with submission of the IND to the FDA as the first milestoneIn yearsAimwill conduct a Phase I single ascending doseSADstudy innormal healthy volunteersNHVand NASH patients followed by multi ascendingday repeat dose studyMADinNHV NASH subjects as the second major milestoneThis First in Human study will establish the safe dose rangetolerability and PK PD efficacy of OAi using ex vivo PARassays and biomarkers and will inform the design and endpoints of Phasestudies to be conducted in the NASH populationProject NarrativeNonalcoholic steatohepatitisNASHcirrhosis is one of the leading indications for liver transplantation in the United States with an estimatedmillion Americans suffering from NASHProtease activated receptorPARhas been identified as an emerging therapeutic opportunity for the effective and safe treatment of NASH as a non invasive pharmacologic therapyThis proposal provides the blueprint for completion of the IND development of a first in class PARPepducinOAiand evaluates the safety and pharmacology of the drug in a Phase I clinical trialthereby advancing a new and potentially effective treatment of NASH